The present invention relates generally to the fields of nutrition and obstetrics. More particularly, the present invention relates to a dietary supplement for use in humans, and in particular, in pregnant or lactating women, which supplement comprises calcium citrate and carbonyl iron. Compositions and methods for enhancing uptake of calcium, zinc, magnesium, or iron for a human are also provided.
Vitamin and mineral compositions are commonly taken as dietary aids either as therapeutic preparations directed to a specific medical problem or as general nutritional supplements. Daily requirements for vitamins and minerals vary depending upon such factors as sex, body size, growth rate, exercise, disease, and age. Such compositions are especially provided for pregnant or lactating women to ensure provision of adequate nutrients for the developing fetus and for the mother.
Supplements pose a potential problem of nutrientxe2x80x94nutrient interactions. An excess of one nutrient in a supplement may interact with another nutrient in the supplement, thereby affecting absorption adversely, or less often, beneficially. For example, iron is reported to inhibit the absorption of zinc (Hambridge et al., Obstet. Gynecol. 4:593-596, 1987), zinc is reported to inhibit the absorption of copper (Festa et al., Am. J. Clin. Nutr. 41:285-292, 1985), calcium is reported to interfere with the absorption of both iron and zinc (Seligman et al., Obstet. Gynecol. 61:356-362, 1983), and protein is reported to increase urinary calcium losses (Allen et al., Am. J. Clin. Nutr. 32:741-749, 1979) and vitamin B6 requirements (National Research Council, Recommended Dietary Allowances, 10th ed., Natl. Acad. Press, Washington, D.C. 1989)
Calcium is required for adequate bone formation and maintenance, as well as for diverse metabolic functions. Approximately 99% of the calcium in the human body is located in the skeleton. Women are advised to increase their calcium intake substantially during pregnancy, and concern exists regarding many pregnant women who do not ingest enough calcium to maintain their own skeletons while providing for fetal needs. An estimated 600-800 mg of calcium is ingested in an average diet, far below the recommended dietary allowance. The efficiency of calcium absorption is determined by several factors, including the chemical form of ingested calcium. Part of the absorbed calcium is eliminated in urine, which poses a problem for certain people who are prone to the formation of calcium-containing kidney stones.
Ingested calcium is absorbed across the wall of the gastrointestinal tract and, in particular, the upper small intestine. To be absorbed across the intestinal wall, calcium must be soluble as an ionized form or as a salt form. Two major factors affect the amount of soluble calcium in the gastrointestinal tract. The first factor is gastric acid secretion, which increases the solubility of calcium by lowering the pH of intestinal fluids. This is important because ingested calcium is typically in the form of relatively insoluble salts, such as calcium carbonate and calcium phosphate. The second factor determining calcium absorption is the secretion of bicarbonate from the pancreas into the small intestine. The bicarbonate secreted into the small intestine alkalinizes fluid contained in the intestine, thereby decreasing the solubility of calcium. The absorption of calcium from the small intestine under a number of conditions varies with the form of ingested calcium salt. Minerals such as zinc and iron also depend upon stomach acid to become solubilized for intestinal absorption. Calcium in the form of calcium carbonate decreases the absorption of those minerals because of neutralization of the acidic environment.
Intestinal calcium absorption was reported to be increased almost 25% in women when the calcium was administered in the form of calcium citrate as compared to calcium carbonate (Harvey et al., J. Am. Coll. of Nutr., 9(6):583-587, 1990.) In another study, performed in healthy, post-menopausal women, supplementation with calcium citrate was reported to be more effective than supplementation with equimolar amounts of calcium carbonate (Dossen-Use et al., N. Eng. J. Med., 323:878-83, 1990.) In patients with decreased gastric acid secretion, intestinal calcium absorption was reportedly ten-fold higher when calcium was administrated as a citrate salt as compared to a bicarbonate salt (Recker et. al., N. Eng. J. Med., 313:70-73, 1965.) Despite the higher intestinal absorption of calcium when administered in the form of calcium citrate, the use of calcium citrate actually was reported to decrease the propensity for the crystallization of calcium oxalate in the urine (Harvey et al., J. Clin. Endocrin. and Metab., 61(6):1225-1233.
Calcium citrate is an efficiently absorbable chemical form of calcium. Because of improved absorption of calcium, osteoporosis development is precluded. Citrate is a known inhibitor of calcium stone formation, therefore, the risk of calcium nephrolithiasis (resulting from calcium supplementation) is reduced. An especially dense form of calcium citrate having advantageous properties regarding solubility and bioavailability is ULTRADENSE(trademark) calcium citrate as described in U.S. Pat. Nos. 4,814,177; 4,851,221; and 4,772,467, incorporated by reference herein, and marketed under the tradename CITRACAL(copyright). CITRACAL(copyright) with vitamin D is also available.
Accidental overdoses of iron-containing supplements are the most common cause of poisoning death in children under six. The FDA, Consumer Product Safety Commission, and American Association of Poison Control Centers are actively developing new regulations seeking to correct this significant public health issue which has seen the number of reported accidental iron ingestions in children more than double, to over 110,000, in the last decade.
Safety of iron supplements is a significant public health issue. Since 1986 at least 38 children between the ages of 9 months and 3 years have died from accidental ingestion of iron supplement products according to the American Association of Poison Control Centers. Over this same time frame, the FDA has recorded more than 110,000 incidents of pediatric iron overdose, and iron poisoning has become the number one cause of poisoning death in children. Ferrous salts, commonly used in prenatal vitamin preparations, can produce toxic symptoms at ingestion levels as low as 25 mg/kg and significant iron poisoning at levels as low as 60 mg/kg.
Alternatively, elemental iron may be supplied in a supplement as carbonyl iron. The term xe2x80x9ccarbonyl ironxe2x80x9d is from a manufacturing process in which gaseous iron pentacarbonyl is heated under controlled conditions to extremely high temperatures resulting in the deposition of submicroscopic particles of 98% pure elemental iron that aggregate into spheres having a diameter of from about 2-8 microns (average of 5 microns). The importance of the small size is that carbonyl iron particles have very large surface areas since this property varies inversely with the size of a particle. The larger surface area results in higher reactivity of carbonyl iron particles with gastric acid in the stomach and consequently higher absorption rates. Thus, carbonyl iron exhibits 2-5 times higher bioavailability than other elemental iron forms (Sacks and Houchin, Am. J. Clin. Nutr. 31:566-571, 1978). Studies in laboratory animals and humans show that carbonyl iron is as well absorbed as ferrous sulfate and ferrous fumarate without the attendant risk of iron toxicity. Carbonyl iron has been marketed under the name FERRONYL(copyright) IRON.
Within the stomach, carbonyl iron is oxidized to the ferrous form of iron using naturally produced stomach acids. This provides a delayed-release mechanism regulated by the body""s own acid secretion. Because of its natural, self-regulated delayed release, carbonyl iron is significantly safer than other ferrous iron salts used in ordinary prenatal vitamins. In animal studies, carbonyl iron had an LD0 (the dose where all animals survive) of 10,000 to 15,000 mg/kg of iron, and an LD100 (the dose where all animals died) of 50,000 to 60,000 mg/kg of iron (Shelanski, Bull Nat Formulary Committee, 1980, 18:87-94). This represents a level of safety at least 100 times higher than traditional ferrous salts, with a therapeutic profile that is similar to that of ferrous salts. Iron replenishment studies in human subjects using doses of carbonyl iron up to 3,000 mg daily (approximately 15 times the usual dose of ferrous sulfate iron) have confirmed this remarkable safety profile (Gordeuk et al., Blood, 1986; 67:745-752).
Iron supplementation can produce epigastric distress. In studies with female blood donors using doses of carbonyl iron 10 times higher than normal doses of ferrous sulfate, the incidence of gastrointestinal side effects was equivalent (Gordeuk et al., Am J Clin Nutr, 1987; 46:1029-1034). The iron needs of females who donate blood more than three times a year are believed to closely mimic the iron needs during pregnancy. The ability to tolerate significantly higher doses of carbonyl iron in these blood donors lead to faster restoration of iron stores. Even at extremely high doses of carbonyl iron, there have been no reports of iron overload.
EP publication EP 0702954 relates to a calcium dietary supplement comprising a calcium salt, vitamin D and at least one mineral; where the calcium salt may be calcium citrate. Bronson Vitamins and Herbals (Winter/Spring 1996 catalog) describes a prenatal II (or #2) supplement that contains 125 mg of calcium (citrate) and 30 mg of iron (FERRONYL(copyright)). Calcium at a level of 125 mg is only 10% of the recommended dietary allowance for pregnant or lactating women.
Because of the above difficulties with safety regarding iron supplements, undesired interactions in competing for stomach acid, and use of suboptimal forms of calcium, the present inventors provide herein an improved single oral dosage supplement that contains unprecedented levels of calcium in a form that is ready solubilized in vivo, together with carbonyl iron to provide a safe and effective dietary supplement. Further vitamins and minerals can be included and, when included, provides a single oral dosage form containing calcium, iron and the recommended dietary allowance of a number of vitamins and minerals in a tablet that is small enough for easy swallowing, thereby, encouraging patient acceptance. Further advantages will become apparent in this disclosure.
The present invention provides a dietary supplement comprising calcium citrate and carbonyl iron. ULTRADENSE(trademark) calcium citrate provides a greater amount of calcium in a form that enhances absorption of iron, zinc, and magnesium compared to usual calcium citrate; and uses carbonyl iron to provide iron in a form that significantly reduces the risk to children of accidental iron poisoning from formulations that provide iron in salt form. A further supplement of the invention comprises iodine; zinc; folic acid; copper; vitamins A, D, E, C, B1, B2, B6, B12; and niacinamide.
A calcium citrate composition having a bulk density between 0.8 g/cc and 1.3 g/cc, preferably between 1.05 g/cc and 1.25 g/cc and most preferably between about 1.1 g/cc and 1.2 g/cc may be produced by methods of the present invention. Citric acid and a calcium compound selected from the group consisting of calcium carbonate, calcium oxide and calcium hydroxide are mixed to produce a mixture having a calcium compound/citric acid molar ratio of about 1.5. A hydrated mixture with a moisture content between about 30.5 weight percent and about 47.5 weight percent is produced by agitatively adding water to the mixture, although when desired the calcium compound, citric acid and water may be mixed in one step. The hydrated mixture is then blended to facilitate the reaction of citric acid with the calcium compound and to form a granulated mass primarily consisting of granules with diameters between about {fraction (1/64)} inch and about {fraction (1/16)} inch.
The granulated mass is then dried to a moisture content of between about 10 weight percent and about 13 weight percent to produce a calcium citrate composition having a bulk density greater than about 1.1 g/cc.
Calcium citrate tablets formed as described herein are generally greater than about 15 weight percent calcium and most usually have a calcium/citrate molar ratio of about 3/2. Such tablets preferably have a density greater than about 1.5 g/cc and may, for aesthetic or other purposes, be coated by conventional means with mixtures comprising substances such as sugar, polyvinylpyrrolidone, calcium carbonate and titanium dioxide, for example.
In a further embodiment of the invention, the supplement takes advantage of the density of ULTRADENSE(trademark) calcium citrate and the tablet space saved by using carbonyl iron to provide a single oral tablet dosage form having the following minerals and vitamins: iodine; zinc; copper, folic acid; vitamins A, D, E, C, B1, B2, B6, B12; and niacinamide. The tablet also has the elegance of small size, weighing less than about 1.6 g, and consequent patient acceptability.
A vitamin and mineral dietary supplement comprising calcium citrate wherein the calcium citrate provides from about 100 to 300 mg calcium, carbonyl iron wherein the carbonyl iron provides from about 30 to 120 mg iron, and a vitamin is a further embodiment of the invention. A particularly preferred embodiment is a vitamin and mineral dietary supplement comprising calcium citrate, carbonyl iron, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, vitamin E, folic acid, iodine, copper, zinc, and niacinamide. The supplement also may comprise pharmaceutically acceptable carriers and excipients.
A method of making a vitamin and mineral dietary supplement comprising calcium citrate, carbonyl iron, and a vitamin is a further aspect of the invention. The method comprises the steps of: i) granulating calcium citrate with a first granulating agent to form a first granular mixture; ii) granulating Vitamin E, docusate Na, zinc, copper, and carbonyl iron with a second granulating agent to form a second granular mixture; iii) blending the first mixture with the second mixture in a blender to form a first blend; iv) adding carbonyl iron, vitamin A, vitamin B1, vitamin B2, vitamin B6, vitamin B12, vitamin C, vitamin D, folic acid, iodine, and niacinamide to the first blend; v) blending the first blend and added ingredients to form a second blend; and vi) formulating the second blend into an oral dosage form. A composition of matter comprising the second blend made by the abovedescribed process is also an embodiment of the invention.
In this method, the granulating agents have the properties of providing cohesion to form a granular material that allows formation of tablets having optimal dissolution characteristics. Granulating agents include, but are not limited to, ethyl cellulose, povidone, polyethylene glycol, shellac, methylcellulose, hydroxypropylmethylcellulose, or the like. When the first granulating agent is ethyl cellulose, the ethyl cellulose is present in a ratio to calcium citrate of about 2:98. A preferred second granulating agent is povidone in alcohol. An important aspect of the invention is that the second blend has a bulk density of about 0.9 to 1.1 g/cc.
A method of treating a vitamin or mineral deficiency or anticipated deficiency of a human is a further aspect of the invention. The method comprises the steps of obtaining a vitamin and mineral supplement as provided herein, and administering the supplement to the human having a vitamin or mineral deficiency. In particular, the human is pregnant or lactating, the human is a blood donor, or the human is anemic. A particular advantage for pregnant women is that the supplement enhances uptake of magnesium from the diet; magnesium sulfate in bolus form has long been used for preventing premature labor. Example 3 provides data demonstrating the enhanced uptake of magnesium.
A method of enhancing uptake of calcium, magnesium, iron, or zinc in a human comprising the steps of obtaining a vitamin and mineral supplement as provided herein, and administering the supplement to the human in need of enhanced uptake of calcium, magnesium, iron or zinc is a further aspect of the invention.